A pancancer analysis of impact of <i>MDM2/MDM4</i> on immune checkpoint blockade (ICB).
Authors: Wafik S. El-Deiry, Taylor Arnoff, Ilyas Sahin, Hossein Borghaei, Vivek Subbiah, Hina Khan, Benedito A. Carneiro, Howard Safran, Stephanie L. Graff, Don S. Dizon, Elisabeth I. Heath, Eric T. Wong, Abbas Abbas, Christopher G. Azzoli, Michael J. Demeure, Jim Abraham, Razelle Kurzrock, Joanne Xiu, Emil Lou, Stephen V. Liu
Journal: Journal of Clinical Oncology (2022)

2630 Background: MDM2/MDM4 are implicated in hyperprogression after immune checkpoint blockade (ICB). Our preclinical studies showed reduced T-cell killing of MDM2-amplified tumor cells that was overcome by an MDM2 antagonist or gene knockdown, and we observed additional tumor killing by T-cells with MDM2 inhibition plus anti-PD1. We hypothesized that MDM2/4 gene amplification/overexpression correlates with resistance to ICB and investigated the association of MDM2/4 alterations to overall survival (OS) following ICB across multiple solid tumors. Methods: Solid tumors tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing on DNA (NGS) were analyzed. MDM2/4 amplification (amp) was tested by NGS and determined as either amp4 (cutoff of &gt;=4.0 copies) or amp6 (&gt;=6.0) or amp8 (&gt;=8.0). Real-world OS was obtained from insurance claims data and calculated from treatment start or tissue collection to last contact. Kaplan-Meier estimates were calculated for molecularly defined groups. X 2 /Fisher-Exact were used and significance determined as P-value adjusted for multiple comparisons (q&lt;0.05). Results: In a large cohort of TP53-wild type solid tumors, 2785 had MDM2 amp4 (262 were ICB-treated), 2108 had MDM2 amp6 (ICB: 192), 1721 had MDM2 amp8 (ICB: 149); 1040 tumors had MDM4 amp4 (ICB: 59), 293 had MDM4 amp6 (ICB: 8) and 217 had amp8 (ICB: 4). NSCLC, GBM, breast, bladder cancer and liposarcoma had the highest MDM2 amp and breast cancer, GBM, uterine, NSCLC and ovarian cancers had the highest MDM4 amp. When all tumors were considered, MDM2 amp4, 6 and 8 significantly associated with shortened OS (amp4: HR 1.31; amp6: HR 1.31; amp8: 1.29, all p&lt;0.0001); similar results were seen with MDM4 (amp4: HR 1.14, p=0.004; amp6: HR 1.51, p&lt;0.00001 and amp8: HR 1.6, p&lt;0.00001). Of note, MDM4 amp4 but not MDM2 amp4 was associated with significantly worse post-ICB survival (HR: 1.55, p=0.009).When comparing molecular differences between MDM2 amp4 and MDM4 amp4, significantly higher PDL1 expression was associated with MDM2 amp (Ab clone 28.8: 58% vs. 28%; clone 22c3: 48% vs.25%, q&lt;0.05); while higher mutation rates of ARID1A, PIK3CA, PTEN, KRAS and CTNNB1 were associated with MDM4 amp (all q&lt;0.05). When investigating NSCLC, MDM4 amp4 was associated with decreased post-ICB survival in NSCLC (HR: 2.59, p=0.001) but not MDM2; when comparing the molecular alterations, MDM2 amp was associated with significantly higher PDL1 (22c3) (54% vs. 27%), EGFR mutation (36% vs. 14%) but less prevalent KRAS (15% vs. 50%), STK11 (11% vs. 41%), KEAP1 (2.5% vs. 27%) and BRAF (2% vs. 16%) mutations. The association with poor prognosis of MDM2 amp4/6 (HR: 1.2 and 1.3, p&lt;0.05) and MDM4 amp4/6 (HR: 1.3 and 1.6, p&lt;0.05) was seen in breast cancer, but not in NSCLC, GBM, bladder or uterine cancers. Conclusions: MDM2 and MDM4 amplification are negative prognostic factors in TP53-WT breast cancer while MDM4 amp is associated with reduced survival in ICB-treated NSCLC.